1. Field of the Invention
Azitromycin is the USAN generic name of the product 9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, which constitutes the first example of a new class of antibiotics (azalides) and is an effective therapeutic agent in the treatment of sexually transmitted diseases, infections of the respiratory apparatus and infections of the skin (H. A. Kirst, G. D. Sides, Antimicrob. Agents Chemother, 1989, 33, 1419-1422).
2. Description of the Prior Art
FIG. 1 shows the bibliographical background in relation to the synthesis of this macrolide. Azitromycin was first described by S. Djokic and G. Kobrehel in the Belgian Pat. No. 892,357 and in its related U.S. Pat. No. 4,517,359, obtained by means of the reductive alkylation of 9-deoxo-9a-aza-9a-homoerythromycin A (3), by treatment of said amine with a mixture of formic acid and aqueous formaldehyde under chloroform reflux, following the classical experimental conditions of the Eschweller-Clarke reaction.
The synthesis of 9-deoxo-9a-aza-9a-homoerythromycin A (3), is described by S. Djokic and G. Kobrehel in U.S. Pat. No. 4,328,334, and in the J. Chem. Soc. Perkin Trans I, 1986, 1881. In these publications, the product is found denominated as 10-dihydro-10-deoxo-11-azaerythromycin A, and it is obtained by a synthetic sequence which schematically consists of: Obtaining the oxime of erythromycin A (1) by reaction of erythromycin A hydroxylamine hydrochloride. Obtaining the iminoether 9-deoxo-6-deoxy-6,9-epoxy-9,9a-dihydro-9a-azahomoerythromycin A (2) by a transposition of the oxime of erythromycin A (1). This iminoether and the process for obtaining it is also described in Pat. WO 94/26758 and in Eur. Pat. 0,137,132. In U.S. Pat. No. 4,328,324 this iminoether is erroneously assigned the structure of the lactam obtained by a Beckman transposition starting from the oxime of erythromycin. Obtaining 9-deoxo-9a-aza-9a-homoerythromycin A (3) by reduction of the iminoether (2) with sodium borohydride in methanol, or by catalytic hydrogenation in the presence of platinum dioxide with acetic acid as a solvent.
In the literature previously mentioned, the reduction of the iminoether 9-deoxo-6-deoxy-6,9-epoxy-9,9a-dihydro-9a-azahomoerythromycin A (2) can be carried out by following two different methods:
a) Reduction with sodium borohydride in methanol at 0.degree. C. This method presents a number of drawbacks: methanol destroys the reducing agent, and some of the steps which include the isolation of the reaction product (azaerythromycin) affect the quality of the same. The literature previously cited describes how, in the presence of acid aqueous media, azaerythromycin (3) becomes partially hydrolysed to yield deosaminylazaerythromycin (6) (S. Djokic et al. in J. Chem. Soc. Perkin Trans I, 1986, 1881). PA0 b) Catalytic hydrogenation with platinum dioxide, at high pressures (70 atm). The drawbacks of this method, from the point of view of its industrial application are obvious: the high working pressures and the manipulation of platinum dioxide. PA0 a) The dehydrate form keeps its percentile water content constant at values (4,5-5%) which are very close to the theoretical value (4,6%). PA0 b) Thermogravimetric analysis (TGA) of azitromycin dihydrate indicates a total weight loss of between 4,5 and 5% at 200.degree. C., yielding a plot with no inflections throughout the whole process. PA0 c) The differential calorimetry analysis (DSC) of azitromycin dehydrate reveals the presence of a single endotherm which may vary between 126.degree. and 135.degree. C., with an energy absorbed during the process which ranges between 27 and 34 cal/g. PA0 d) The infrared spectra in KBr of both crystalline forms presents clear differences:
The Eschweiler-Clarke reaction employed in U.S. Pat. No. 4,517,359 and in the J. Chem. Res., 1988, 132; and idem miniprint., 1988, 1239, for preparing azitromycin (4) results in the formation of some reaction impurities such as the case of the formamide derived from the amine 9-deoxo-9a-aza-9a-homoerythromycin A.
The structural elucidation studies of azitromycin (4) (S. Djokic and G. Kobrehel J. Chem. Res., 1988, 132; and idem miniprint., 1988, 1239) have demonstrated its existence in two crystalline forms: hygroscopic monohydrate (4) and non-hygroscopic crystalline dihydrate (5). The latter is the preferred form for its manipulation with the object of producing formulations of therapeutic use, as described in the Eur. Pat. No. 0,298,650.